Studies indicate that more than 70% of the carnitine present in the plasma of a hemodialysis patient can be removed during a dialysis session. Carnitine is a naturally occurring substance in the human body required for energy metabolism at the cellular level because it transports fatty acid-derivatives into the inner aspect of the mitochondrionia to produce energy and removes various acyl moeities from the mitochondria and cells. Dialytic loss of carnitine by patients undergoing hemodialysis is thought to be attributable to the compound's relatively small molecular weight, high water solubility, and poor protein binding. Carnitine levels are further diminished in end stage renal disease patients by reduced renal synthesis and reduced intake of meat and dairy foods.
Primary and secondary carnitine deficiency syndromes are well-described entities whose clinical sequelae could result in serious illness or death. Carnitine deficiency syndromes are characterized by such diverse symptoms as cardiomyopathy, muscle weakness, lipid storage myopathy, hepatic dysfunction, encephalopathy, failure to thrive, and recurrent infections.
As described in U.S. Pat. No. 6,335,369, the administration of levocarnitine may be beneficially used to treat carnitine deficiency in patients with end stage renal disease (“ESRD”) who are undergoing regular hemodialysis. Chronic uremic patients undergoing periodical hemodialysis are treated with carnitine or one of its salts to prevent or treat carnitine deficiency in patients with end stage renal disease. An effective dose of levocarnitine (the recommended starting intravenous dosage is typically 10-20 mg of drug per kg of patient dry body weight) is administered intravenously via a venous return line after each dialysis session. Initiation of such levocarnitine injection therapy may be prompted by pre-dialysis plasma free carnitine concentrations that are below normal (normal concentrations being approximately 40-50 micromoles/liter (μmol/L)). Such intravenous administration of levocarnitine to end stage renal disease patients on hemodialysis results in increased plasma carnitine concentrations and thereby makes it possible to correct for the loss of plasma carnitine which otherwise takes place during hemodialysis therapy. Importantly, immediately after giving intravenous carnitine to a patient at the end of a dialysis session, carnitine levels in the patient's plasma rise to high levels and then return to a pre-dialysis baseline levels after approximately 10-24 hours (presumably because the carnitine has entered the tissues). In this manner, it is possible to avoid tissue carnitine depletion, which is a long-term consequence of repeated losses of carnitine from plasma that the patient undergoes during successive dialytic sessions over a prolonged period of time.
Prior studies have listed specific subsets of patients in whom intravenously administered carnitine had been associated with improvement in clinical parameters. These subsets of patients have included those with cardiomyopathy, skeletal muscle weakness/myopathy, anemia of uremia unresponsive to or requiring large doses of erythropoietin (EPO), lack of energy (which has a negative effect upon quality of life), severe and persistent muscle cramps, and/or intradialytic hypotensive episodes. Despite these studies, the use of levocarnitine in dialysis patients is sometimes limited.
Cardiomyopathy, muscle weakness, and fatigue are often due to factors other than carnitine deficiency. The ability to methodically analyze these common conditions is critical to the appropriate application of this therapy. Non-critical use of carnitine is both medically incorrect and economically wasteful. Thus, there remains a need in the art for methods to differentiate other etiologies for clinical conditions that have been associated with dialysis related carnitine deficiency and for which intravenous levocarnitine therapy is being considered in the treatment of dialysis patients.